Metabolic changes reveal the development of schistosomiasis in mice - PubMed (original) (raw)
Metabolic changes reveal the development of schistosomiasis in mice
Junfang Wu et al. PLoS Negl Trop Dis. 2010.
Abstract
Schistosomiasis is a parasitic zoonosis caused by small trematode worms called schistosomes, amongst which Schistosoma japonicum (S. japonicum) is endemic in Asia. In order to understand the schistosome-induced changes in the host metabolism so as to facilitate early diagnosis of schistosomiasis, we systematically investigated the dynamic metabolic responses of mice biofluids and liver tissues to S. japonicum infection for five weeks using (1)H NMR spectroscopy in conjunction with multivariate data analysis. We were able to detect schistosomiasis at the third week post-infection, which was one week earlier than "gold standard" methods. We found that S. japonicum infection caused significant elevation of urinary 3-ureidopropionate, a uracil catabolic product, and disturbance of lipid metabolism, stimulation of glycolysis, depression of tricarboxylic acid cycle and disruption of gut microbiota regulations. We further found that the changes of 3-ureidopropionate and overall metabolic changes in both urinary and plasma samples were closely correlated with the time-course of disease progression. Furthermore, such changes together with liver tissue metabonome were clearly associated with the worm-burdens. These findings provided more insightful understandings of host biological responses to the infection and demonstrated that metabonomic analysis is potentially useful for early detection of schistosomiasis and comprehension of the mechanistic aspects of disease progression.
Conflict of interest statement
The authors have declared that no competing interests exist.
Figures
Figure 1. 1H NMR spectra of plasma and liver tissue from control and S. japonicum infected mice.
Typical 500 MHz 1H (CPMG) NMR spectra of plasma obtained from a non-infected BALB/c mouse (A) and a mouse infected with S. japonicum for 5 weeks (B). Typical 600 MHz 1H HRMAS (CPMG) NMR spectra of intact liver tissue obtained from a non-infected mouse (C) and a mouse infected with S japonicum for 5 weeks (D). Keys: 1, valine; 2, leucine; 3, isoleucine; 4, D-3-hydroxybutyrate; 5, lactate; 6, alanine; 7, lysine; 8, acetate; 9, _N_-acetyl-glycoprotein; 10, methionine; 11, acetone; 12, acetoacetate; 13, glutamate; 14, glutamine; 15, citrate; 16, pyruvate; 17, creatine; 18, choline; 19, phosphorylcholine; 20, glyceryl phosphorylcholine; 21a, α-glucose; 21b, β-glucose; 22, lipids; 23, aspartate; 24, trimethylamine-_N_-oxide; 25, taurine; 26, glycine; 27, glycogen; 28; _scyllo_-inositol; U1, unknown1.
Figure 2. 1H NMR spectra of urine samples from control and S. japonicum infected mice.
Typical 600 MHz 1H NMR spectra of urine samples obtained from a non-infected BALB/c mouse (A) and a mouse infected with S. japonicum for 5 week (B). The spectral region, δ 6.7–8.5, was vertically expanded 4 times compared with the aliphatic region (δ 0.7–4.2). Keys: 5, lactate; 8, acetate; 9, _N_-acetyl-glycoproteins; 15, citrate; 16, pyruvate; 17, creatine; 24, trimethylamine-_N_-oxide; 25, taurine; 29, 2-keto-isocaproate; 30, 2-keto-3-methyl-valerate; 31, 2-keto-isovalerate; 32, 2-hydroxyisobutyrate; 33, 2-(4-hydroxyphenyl) propanoic acid; 34, adipate; 35, 4-cresol glucuronide; 36, 3-ureidopropionate; 37, succinate; 38, 2-oxo-glutarate; 39. dimethylamine; 40, trimethylamine; 41, creatinine; 42, malonate; 43, phenylacetylglycine; 44, guanidinoacetate; 45, hippurate; 46, indoxylsulfate; 47, formate; U2,unknown2; U3, unknown3.
Figure 3. O-PLS-DA comparison between NMR spectra of plasma from the S. japonicum infected mice and corresponding controls.
Cross-validated scores (left) and coefficient-coded loadings (right) plots for the comparative O-PLS-DA of plasma data for non-infected and _S. japonicum_-infected mice at different time points. Non-infected (black squares) vs infected (red dots) mice 3 weeks post-infection (A), 4 weeks post-infection (B) and 5 weeks post-infection (C). Non-infected vs lightly infected mice (green) (D) and heavily infected mice (blue) (E) at week 5 post-infection. The colored scale is for coefficients being indicative to the significance of metabolite contributions to the differentiation between classes. Keys: 1, valine; 2, leucine; 3, isoleucine; 4, D-3-hydroxybutyrate; 5, lactate; 6, alanine; 7, lysine; 8, acetate; 9, _N_-acetyl-glycoprotein; 10, methionine; 11, acetone; 12, acetoacetate; 13, glutamate; 14, glutamine; 15, citrate; 16, pyruvate; 17, creatine; 18, choline; 19, phosphorylcholine; 20, glyceryl phosphorylcholine; 21a, α-glucose; 21b, β-glucose; 22, lipid; 23, aspartate; 24, trimethylamine-_N_-oxide; 25, taurine; 26, glycine; 27, glycogen; 28; _scyllo_-inositol; U1, unknown1.
Figure 4. O-PLS-DA comparison between NMR spectra of urine from S. japonicum infected mice and corresponding controls.
Cross-validated scores (left) and coefficient-coded loadings (right) plots for the comparative O-PLS-DA of urine data for non-infected and _S. japonicum_-infected mice at different time points. Non-infected (black boxes) vs infected (red dots) mice 3 weeks post-infection (A), at 4 weeks post-infection (B) and 5 weeks post-infection (C). Non-infected vs lightly infected mice (green) (D) and heavily infected mice (blue) (E) at week 5 post-infection. Keys: 29, 2-keto-isocaproate; 30, 2-keto-3-methyl-valerate; 31, 2-keto-isovalerate; 32, 2-hydroxyisobutyrate; 33, 2-(4-hydroxyphenyl) propanoic acid; 34, adipate; 35, 4-cresol glucuronide; 36, 3-ureidopropionate; 37, succinate; 38, 2-oxo-glutarate; 39. dimethylamine; 40, trimethylamine; 41, creatinine; 42, malonate; 43, phenylacetylglycine; 44, guanidinoacetate; 45, hippurate; 46, indoxylsulfate; 47, formate; U2; unknown2; U3, unknown3.
Figure 5. O-PLS-DA comparison between NMR spectra of liver tissue from the S. japonicum infected mice and controls.
Cross-validated scores (left) and coefficient-coded loadings (right) plots for the comparative O-PLS-DA of the CPMG filtered 1H HRMAS NMR data of liver obtained from control (black boxes) and infected (red dots) mice at week 5 post-infection.
Figure 6. PLS correlation of the NMR spectral data of biofluids and liver tissues with the worm burden.
PLS correlation plot derived from the CPMG filtered 1H NMR data for plasma (R2X = 0.521, Q2 = 0.281) (A), 1H HRMAS NMR data for liver tissue (R2X = 0.541, Q2 = 0.501) (B) and 1H NMR data for urine samples (R2X = 0.455, Q2 = 0.305) (C), which were all obtained from infected mice at week 5 post-infection, against worm burden. The arrows indicated increases in the severity of the infection.
Figure 7. Metabolite concentration changes relative to corresponding controls at different time points after S. japonicum infection.
The insert showed different severity at week 5 post infection. Keys: 3-UP, 3-ureidopropionate; PAG, phenylacetylglycine; 2-Kiv, 2-keto-isovalerate; DMA, dimethylamine; TMA, trimethylamine. Cinf and Ccon stand for the averaged concentration in the infection and control group, respectively. Dashed lines indicated no changes and solid lines were for visual guidance only.
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